Project 1 will consist of a multi-institutional study of patients with von Willebrand disease and will perform a clinical assessment of these patients and 1) determine the linkage of low or abnormal VWF within families, 2) determine genetic mutations in the VWF gene that could result in these clinical manifestations or 3) identify the frequency of inheritable abnormal VWF caused by other genetic loci residing outside the VWF gene. Candidate genes that might cause this will be identified through Projects 3 and 4. When genetic VWF mutations are identified, Project 2 will express the mutant VWF and define the underlying pathophysiologic mechanism(s) in vitro and in vivo. Aim 1 will identify the frequency of VWF gene mutations in patients with the clinical diagnosis of VWD and correlate these to their laboratory testing as well as a clinical scoring system that is a modification of the one used in the European Union Study of VWD. It will determine if the spectrum of genetic mutations causing type 3 VWD (or it's heterozygous carriers differs from those mutations identified in VWFlinked type 1 VWD. Aim 2 will identify the mutations causing variant, type 2 VWD and determine the penetrance of clinical bleeding symptoms with the scoring system used to study type 1 patients. Clinical laboratory phenotyping will be performed to contrast the degree of abnormality in affected, linked family members. Aim 3 will determine the frequency of VWD that is caused by increased plasma clearance that can be detected by comparing plasma levels of the VWF propeptide (VWFpp) to VWF, identifying clearance of VWF released by DDAVP, and will determine the differences between these in blood group O and non-O individuals. Since VWD has been reported to be common in women with menorrhagia, Aim 4 will study the prevalence of low or abnormal VWF in these women compared to age-matched controls. In those with reduced or abnormal VWF, we will determine if the mutation rate and distribution of mutations is similar to those identified in type 1 VWD. Project 1 will lead to a greater understanding of the scope and impact of clinical VWD and its ability to be detected in the clinical and research laboratory.